+

WO2010019953A1 - Préparations anesthésiques locales à concentration élevée - Google Patents

Préparations anesthésiques locales à concentration élevée Download PDF

Info

Publication number
WO2010019953A1
WO2010019953A1 PCT/US2009/054054 US2009054054W WO2010019953A1 WO 2010019953 A1 WO2010019953 A1 WO 2010019953A1 US 2009054054 W US2009054054 W US 2009054054W WO 2010019953 A1 WO2010019953 A1 WO 2010019953A1
Authority
WO
WIPO (PCT)
Prior art keywords
lidocaine
gel
formulation
hours
dose
Prior art date
Application number
PCT/US2009/054054
Other languages
English (en)
Inventor
James N. Campbell
Arthur F. Michaelis
Original Assignee
Arcion Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Arcion Therapeutics, Inc. filed Critical Arcion Therapeutics, Inc.
Publication of WO2010019953A1 publication Critical patent/WO2010019953A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to formulations containing a high concentration of topical anesthetic, such as lidocaine, which can be used for the treatment of pain.
  • topical anesthetic such as lidocaine
  • Controlled release transdermal devices rely for their effect on delivery of a known flux of drug to the skin for a prolonged period of time, generally a day, several days, or a week.
  • Two mechanisms are used to regulate the drug flux: either the drug is contained within a drug reservoir, which is separated from the skin of the wearer by a synthetic membrane, through which the drug diffuses; or the drug is held dissolved or suspended in a polymer matrix, through which the drug diffuses to the skin.
  • Devices incorporating a reservoir will deliver a steady drug flux across the membrane as long as excess undissolved drug remains in the reservoir; matrix or monolithic devices are typically characterized by a falling drug flux with time, as the matrix layers closer to the skin are depleted of drug.
  • Methods for making transdermal patches are described in U.S. Patent Nos. 6,461,644, 6,676,961, 5,985,311, 5,948,433.
  • Lidocaine-containing formulations are described in U.S. Patent Nos. 4,777,046, 5,958,446, 5,719,197, 5,686,099, 5,656,286, 5,474,783, 5,300,291, 4,994,267, 4,814,168, 7,018,647, 6,299,902; and 6,297,290.
  • U.S. Patent Application No. 2009/0048296 describes formulations containing a high concentration of lidocaine in the range of at least 20%, preferably about 40%.
  • Topical gels, plasters, and patches are described in U.S. Patent Nos. 5,411,738, 5,601,838, 5,709,869 and 5,827,829 which are assigned to Endo Pharmaceuticals.
  • the gels described in these patents contain from 2-20% lidocaine, preferably from 1-10% or 5-10% lidocaine.
  • a 5% lidocaine patch marketed as LIDODERM® is available from Endo Pharmaceuticals, Inc.
  • the LIDODERM® patch comprises an adhesive material containing 5% lidocaine, which is applied to a non- woven polyester felt backing and covered with a polyethylene terephthalate (PET) film release liner.
  • PET polyethylene terephthalate
  • This patch is applied only once for up to 12 hours in a given 24 hour period.
  • PET polyethylene terephthalate
  • the marketed patch provides satisfactory therapy to some patients. Delivery of lidocaine in a patch, however, has numerous liabilities for the patient. Since the patch is a finite size and shape, the application area is determined by the patch and not by the dimensions of the painful site.
  • the patch may not necessarily fit the area or be comfortable to the wearer since the patch may not conform to the defect.
  • the patch is difficult to apply to toes and fingers. Applying the patch to the face creates a stigma issue for patients.
  • the patch is undesirable for hair bearing areas as well since hair limits adhesiveness and because of the depillitation that may occur with removal of the patch.
  • the patch may also make the patient warmer, and thus be a burden in hot environments.
  • the delivery of drug from the lidocaine patch is designed to be constant over the 12-hour exposure period. However, it may be therapeutically important to provide a loading dose of drug to eliminate pain quickly when first administering the therapy. It is well known in the treatment of pain that more analgesic is required to treat established pain than is needed to prevent pain from becoming more intense. Such a profile cannot be provided by a patch delivering at a constant rate. It is therefore an object of the present invention to provide topical anesthetic formulations that can he used to provide relief from pain over a period of time.
  • a topical anesthetic formulation containing a high concentration of local anesthetic in a pharmaceutically acceptable carrier for topical application and method of use to ameliorate or inhibit pain, including neuropathic pain, has been developed, such that the target tissue (skin) is appropriately dosed with anesthetic.
  • the formulation is used to treat pain other than neuropathic pain.
  • the local anesthetic is lidocaine, most preferably lidocaine free base, most preferably in a continuous phase gel, although creams, lotions, foams, sprays or ointments may also be used, and the dosage of the local anesthetic is effective in the painful area or immediately adjacent areas, to ameliorate or eliminate the pain.
  • the formulations may release the largest dose of drug shortly after administration, for example, from 0 up to and including about 12 hours after administration, preferably from 0 to 8 hours. In another embodiment, the formulation releases the largest dose of drug from 0 to 6 hours. In a particular embodiment, the formulation provides an initial burst release within two hours. In another particular embodiment, the formulation provides an initial burst release within four hours. In still another particular embodiment, the formulation provides an initial burst release within six hours, and in still another particular embodiment, the formulation provides an initial burst release at about 8 hours. Earlier time period release may result in a more rapid onset of pain relief for the patient.
  • the concentration of the drug in the formulation is from about greater than 20% to about 40% or higher by weight of the formulation. In the preferred embodiment, the concentration is about 40%.
  • the amount of lidocaine in the gel or ointment may be greater than 40, 50 or 60% w/w.
  • the formulation is topically administered to the side in need of treatment thereof.
  • the formulation is applied to the site of, or adjacent to, the painful area. Relief is typically obtained for a period of several hours or days, depending on the dosing schedule.
  • the formulations can be applied once a day or more frequently, such as two times or three times a day.
  • the preparation may be used for local topical delivery to any location where reduction of pain is required or desirable. This would apply to wounds, burns, and areas where medical procedure and cosmetic procedures are done. For example it would be desirable to use a rapidly acting anesthetic in a location where a patient has an abrasion or other skin wound that causes pain. Burns cause pain and it would be desirable to reduce pain quickly but local application of an anesthetic.
  • a single dose irritation/pharmacokinetics study was conducted with White New Zealand Rabbits. AUCo- t increased disproportionately in male and female rabbits when the dermal dose was increased from 30 to 300 mg/kg when lidocaine was delivered using either the ARC-31 or ARC- 32 lidocaine gel, 40% formulation.
  • lidocaine Exposure to lidocaine, as measured using both C ma ⁇ and AUCo- t , was greater in rabbits dosed using the ARC-32 lidocaine gel compared to the ARC-31 lidocaine gel.
  • Figure 1 is a graph of the cumulative penetration of lidocaine from: gels ID:2749-30 ( ⁇ ), ID:2749-32 ( ⁇ ), ID:2749-31 (v), and ID:2749-28 (lidocaine HCl, X); spray ID:2749-72 ( ⁇ ); creams ID:2749-38 ( ⁇ ) and
  • Figure 2 is a graph showing the mean plasma concentration of lidocaine (ng/ml) in White New Zealand Rats administered dermally ARC- 31 Lidocaine GeI 5 40% at a dose of 30 mg/kg ( ⁇ ), 300 mg/kg ( A), and 1000 mg/kg ( ⁇ ) as a function of time (hours) post dose.
  • Figure 2A show the mean plasma concentration in male rabbits and
  • Figure 2B shows the mean plasma concentration in female rabbits.
  • Figure 3 is a graph showing the mean plasma concentration of lidocaine (ng/ml) in White New Zealand Rats administered dermally ARC- 32 Lidocaine Gel, 40% at a dose of 30 mg/kg ( ⁇ ) and 300 mg/kg (A) as a function of time (hours) post dose.
  • Figure 3 A show the mean plasma concentration in male rabbits and Figure 3 B shows the mean plasma concentration in female rabbits.
  • Figure 4 is a graph showing the mean C ma ⁇ (ng/ml) as a function of dose of lidocaine (mg/kg) in White New Zealand Rabbits administered ARC- 31 (male rabbits, o; females rabbits, •) and ARC-32 (male rabbits, A; female rabbits, V).
  • Figure 5 is a graph showing the mean AUCo- t (ng*hr/ml) as a function of dose of lidocaine (mg/kg) in White New Zealand Rabbits administered ARC-31 (male rabbits, o; females rabbits, ⁇ ) and ARC-32 male rabbits, ⁇ ; female rabbits, T).
  • the formulations contain high concentrations of drug applied in a continuous phase directly to the surface of affected skin.
  • "High concentration" means that release of the drug is governed by the Second Law of thermodynamics; rather than Fick's Second Law of Diffusion, which governs the release of drug from dilute solutions.
  • Fick's Second Law of diffusion instructs the rate of release drug from dilute solutions.
  • the result is that a large dose of drug is released in the early time period following administration, for example, 0-12 hours following administration.
  • the formulations may release the largest dose of drug shortly after administration, for example, from 0 up to and including about 12 hours after administration, preferably from 0 to 8 hours. In another embodiment, the formulation releases the largest dose of drug from 0 Io 6 hours.
  • the formulation provides an initial burst release within two hours. In another particular embodiment, the formulation provides an initial burst release within four hours. In still another particular embodiment, the formulation provides an initial burst release within six hours, and in still another particular embodiment, the formulation provides an initial burst release at about 8 hours. Earlier time period release may result in a more rapid onset of pain relief for the patient.
  • High concentration will typically be a concentration of greater than 20% drug/carrier w/w, as discussed in more detail below.
  • the formulation may be a single-phase system such as a gel or a more complex multiphasic system wherein one or more additional phases may be in dynamic equilibrium with the continuous phase. Examples of such systems include creams, lotions, emulsions of lipid containing droplets throughout a continuous aqueous phase, stable micellar dispersions, combinations of an emulsion with excess drug particles distributed throughout, and self-emulsifying systems.
  • the common attribute of the various formulations would be the very high concentration of the drug in the continuous phase of the system. As discussed above, Fick's Second Law of Diffusion governs release of drug from dilute solutions.
  • Removal of the drug from the continuous phase results in an increase in the entropy of the continuous phase as lowering concentration of the drug allows for more movement of the solvent molecules (i.e., increase in entropy) and, thus, an overall decrease in the energy of the system.
  • the result is rapid early time delivery of the drug from the drug product to the target tissues.
  • a highly concentrated gel formulation provided higher early time (e.g. first six hours) levels of drug transport across the human skin membranes than does the reference lidocaine patch (5% drug content) or the lidocaine hydrochloride creams which have only very low effective levels of lidocaine free base (the uncharged base can cross the barrier membranes whereas the charged salt form can not) ⁇ see the Examples).
  • a highly concentrated gel formulation exhibited a nearly identical level of drug transport across the human skin membranes compared to the reference lidocaine patch (5% drug content) ⁇ see the Examples).
  • local anesthetic means a drug which provides local numbness or pain relief. Local anesthetics cause reversible blockage of conduction and/or initiation of action potentials typically by actions related to the interference with voltage gated sodium channels. Lipid solubility appeal's to be the primary determinant of intrinsic anesthetic potency. Chemical compounds which arc highly lipophilic tend to penetrate the nerve membrane more easily, such that fewer molecules are required for conduction blockade resulting in enhanced potency.
  • esters or amides Chemically most local anesthetics are esters or amides.
  • Esters include, but are not limited to, procaine, tetracaine, and chloroprocaine. They are hydrolyzed in plasma by pseudo-cholinesterase.
  • Amides include, but are not limited to, lidocaine, mepivicaine, prilocaine. bupivacaine, and etidocaine. These compounds are often referred to as the "came alkaloids”.
  • Caine alkaloids generally have high first pass metabolisms. The liver rapidly metabolizes the drug and the kidneys excrete the metabolites and/or unchanged drug.
  • anesthetic can be used, including dibucaine, bupivacaine, etidocaine, tetracaine, lidocaine, and xylocaine.
  • the anesthetic is lidocaine, most preferably in the form of the free base, although it may be possible to use a salt, for example, the hydrochloride, hydrobromide, acetate, citrate, or sulfate salt.
  • a salt for example, the hydrochloride, hydrobromide, acetate, citrate, or sulfate salt.
  • gels containing lidocaine free base and creams and sprays containing lidocaine HCl were prepared.
  • the more hydrophilic hydrochloride salt displays longer and denser nerve block, more complete release from matrices, slower clearance from the targeted nerve area, and less encapsulation.
  • the formulations described herein should deliver a high local concentration with little systemic absorption, which should minimize the adverse side effects associated with the systemic absorption of caine alkaloids.
  • the formulations contain from greater than about 20% to about 60% of the drug by weight of the formulation.
  • the formulation contains about 40% by weight of lidocaine, most preferably of the free base.
  • More of the salt form is required to achieve the same transdermal uptake, based on the studies in the following examples.
  • the concentration and pharmacokinetics are dependent on the form of the local anesthetic and the excipient, as discussed in more detail below and demonstrated by the examples. In general, a lower concentration of lidocaine free base in a gel will provide equivalent uptake as a higher concentration of lidocaine HCl in a multiphasic excipient.
  • Water Soluble refers to substances that have a solubility of greater than or equal to 5g /100ml water.
  • Lipid Soluble refers to substances that have a solubility of greater than or equal to 5g / lOOml in a hydrophobic liquid such as castor oil.
  • Hydrophobic liquid such as castor oil.
  • Hydrophilic refers to substances that have strongly polar groups that readily interact with water.
  • Lipophilic refers to compounds having an affinity for lipids.
  • Amphiphilic refers to a molecule combining hydrophilic and lipophilic (hydrophobic) properties
  • Hydrophobic as used herein refers to substances that lack an affinity for water; tending to repel and not absorb water as well as not dissolve in or mix with water.
  • a “gel” is a colloid in which the dispersed phase has combined with the continuous phase to produce a semisolid material, such as jelly.
  • An “oil” is a composition containing at least 95% wt of a lipophilic substance. Examples of lipophilic substances include but are not limited to naturally occurring and synthetic oils, fats, fatty acids, lecithins, triglycerides and combinations thereof.
  • a “continuous phase” refers to the liquid in which solids are suspended or droplets of another liquid are dispersed, and is sometimes called the external phase. This also refers to the fluid phase of a colloid within which solid or fluid particles are distributed. If the continuous phase is water (or another hydrophilic solvent), water-soluble or hydrophilic drugs will dissolve in the continuous phase (as opposed to being dispersed). In a multiphase formulation (e.g., an emulsion), the discreet phase is suspended or dispersed in the continuous phase.
  • An “emulsion” Is a composition containing a mixture of non-miscible components homogenous Iy blended together. In particular embodiments, the non-miscible components include a lipophilic component and an aqueous component.
  • An emulsion is a preparation of one liquid distributed in small globules throughout the body of a second liquid.
  • the dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase.
  • oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in- water emulsion
  • water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase
  • water-in-oil emulsion Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients.
  • Preferred excipients include surfactants, especially non-ionic surfactants; emulsifying agents, especially emulsifying waxes; and liquid non-volatile non-aqueous materials, particularly glycols such as propylene glycol.
  • the oil phase may contain other oily pharmaceutically approved excipients.
  • materials such as hydroxylated castor oil or sesame oil may be used in the oil phase as surfactants or emulsifiers.
  • “Emollients” are an externally applied agent that softens or soothes skin and are generally known in the art and listed in compendia, such as the "Handbook of Pharmaceutical Excipients", 4 th Ed., Pharmaceutical Press, 2003.
  • the emollients are ethylhexylstearate and ethylhexyl palrmtate.
  • “Surfactants” are surface-active agents that lower surface tension and thereby increase the emulsifying, foaming, dispersing, spreading and wetting properties of a product.
  • Suitable non-ionic surfactants include emulsifying wax, glyceryl monooleate, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polysorbate, sorbitan esters, benzyl alcohol, benzyl benzoate, cyclodextrins, glycerin monostearate, poloxamer, povidone and combinations thereof.
  • the non-ionic surfactant is stearyl alcohol.
  • Emmulsifiers are surface active substances which promote the suspension of one liquid in another and promote the formation of a stable mixture, or emulsion, of oil and water. Common emulsifiers are: metallic soaps, certain animal and vegetable oils, and various polar compounds.
  • Suitable emulsifiers include acacia, anionic emulsifying wax, calcium stearate, carbomers, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, ethylene glycol palmitostearate, glycerin monostearate, glyceryl monooleate, hydroxpropyl cellulose, hypromellose, lanolin, hydrous, lanolin alcohols, lecithin, medium-chain triglycerides, methylcelMose, mineral oil and lanolin alcohols, monobasic sodium phosphate, monoethanolamine, nonionic emulsifying wax, oleic acid, poloxamer, poloxamers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, propylene glycol alginate, self-emulsifying glyceryl monostearate, sodium citrate dehydrate, sodium lauryl
  • the emulsifier is glycerol stearate.
  • a “lotion” is a low- to medium-viscosity liquid formulation.
  • a lotion can contain finely powdered substances that are in soluble in the dispersion medium through the use of suspending agents and dispersing agents.
  • lotions can have as the dispersed phase liquid substances that are immiscible wit the vehicle and are usually dispersed by means of emulsifying agents or other suitable stabilizers.
  • the lotion is in the form of an emulsion having a viscosity of between 100 and 1000 centistokes. The fluidity of lotions permits rapid and uniform application over a wide surface area. Lotions are typically intended to dry on the skin leaving a thin coat of their medicinal components on the skin's surface.
  • a “cream” is a viscous liquid or semi-solid emulsion of either the "oil-in-water” or “water-in-oil type”. Creams may contain emulsifying agents and/or other stabilizing agents. In one embodiment, the formulation is in the form of a cream having a viscosity of greater than 1000 centistokes, typically in the range of 20,000-50,000 centistokes. Creams are often time preferred over ointments as they are generally easier to spread and easier to remove.
  • An emulsion is a preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase.
  • oil When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion.
  • the oil phase may consist at least in part of a propellant, such as an HFA propellant.
  • Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients.
  • Preferred excipients include surfactants, especially non-ionic surfactants; emulsifying agents, especially emulsifying waxes; and liquid non-volatile non-aqueous materials, particularly glycols such as propylene glycol.
  • the oil phase may contain other oily pharmaceutically approved excipients.
  • materials such as hydroxylated castor oil or sesame oil may be used in the oil phase as surfactants or emulsifiers.
  • a sub-set of emulsions are the self-emulsifying systems.
  • These drug delivery systems are typically capsules (hard shell or soft shell) comprised of the drug dispersed or dissolved in a mixture of surfactant(s) and lipophillic liquids such as oils or other water immiscible liquids.
  • capsules hard shell or soft shell
  • surfactant(s) and lipophillic liquids such as oils or other water immiscible liquids.
  • Creams are typically thicker than lotions, may have various uses and often one uses more varied oils/butters, depending upon the desired effect upon the skin.
  • the water-base percentage is about 60-75 % and the oil-base is about 20-30 % of the total, with the other percentages being the emulsifier agent, preservatives and additives for a total of 100 %.
  • Examples of the composition of lidocaine/lidocaine hydrochloride creams are shown in the examples.
  • an “ointment” is a semisolid preparation containing an ointment base and optionally one or more active agents.
  • suitable ointment bases include hydrocarbon bases (e.g., petrolatum, white petrolatum, yellow ointment, and mineral oil); absorption bases (hydrophilic petrolatum, anhydrous lanolin, lanolin, and cold cream); water-removable bases (e.g., hydrophilic ointment), and water-soluble bases (e.g., polyethylene glycol ointments).
  • Pastes typically differ from ointments in that they contain a larger percentage of solids. Pastes are typically more absorptive and less greasy that ointments prepared with the same components.
  • a "gel” is a semisolid system containing dispersions of small or large molecules in a liquid vehicle that is rendered semisolid by the action of a thickening agent or polymeric material dissolved or suspended in the liquid vehicle.
  • the liquid may include a lipophilic component, an aqueous component or both.
  • Some emulsions may be gels or otherwise include a gel component.
  • Some gels, however, are not emulsions because they do not contain a homogenized blend of immiscible components. Examples of the composition of lidocaine/lidocaine hydrochloride gels are shown in the examples.
  • Suitable gelling agents include, but are not limited to, modified celluloses, such as hydroxypropyl cellulose and hydroxyethyl cellulose; Carbopol homopolymers and copolymers; and combinations thereof.
  • Suitable solvents in the liquid vehicle include, but are not limited to, diglycol monoethyl ether; alklene glycols, such as propylene glycol; dimethyl isosorbide; alcohols, such as isopropyl alcohol and ethanol. The solvents are typically selected for their ability to dissolve the drug.
  • Other additives which improve the skin feel and/or emolliency of the formulation, may also be incorporated.
  • additives include, but are not limited, isopropyl rnyristate, ethyl acetate, C 12-Cl 5 alkyl benzoates, mineral oil, squalane, cyclomethicone, capric/caprylic triglycerides, and combinations thereof.
  • Foams consist of an emulsion in combination with a gaseous propellant.
  • the gaseous propellant consists primarily of hydrofluoroalkanes (HFAs).
  • HFAs hydrofluoroalkanes
  • Suitable propellants include HFAs such as 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3.3-heptafluoropropane (HFA 227), but mixtures and admixtures of these and other HFAs that are currently approved or may become approved for medical use are suitable.
  • the propellants preferably are not hydrocarbon propellant gases which can produce flammable or explosive vapors during spraying.
  • the compositions preferably contain no volatile alcohols, which can produce flammable or explosive vapors during use.
  • Buffers are used to control pH of a composition.
  • the buffers buffer the composition from a pH of about 4 to a pH of about 7.5, more preferably from a pH of about 4 to a pH of about 7, and most preferably from a pH of about 5 to a pH of about 7.
  • the buffer is triethanolamine.
  • Preservatives can be used to prevent the growth of fungi and microorganisms.
  • Suitable antifungal and antimicrobial agents include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, and thimerosal.
  • the formulations described herein can be administered at or adjacent to the sites of pain to provide relief.
  • the formulations can be administered once a day, for example, for fast, temporary pain relief, or more frequently, such as twice or three times a day, to maintain pain relief over an extended period of time.
  • composition is applied topically to a site at or adjacent to a painful region.
  • the composition is reapplied as necessary.
  • the dosing is applied to the painful skin and subcutaneous structures in order to effect pain relief while avoiding the side effects associated with systemic delivery. Pain relief is obtained within minutes to hours and lasts for periods of approximately three to six hours to 24 hours.
  • the compounds are applied such that the dosage is sufficient to provide an effective dose in the painful area or immediately adjacent areas, to ameliorate or eliminate pain and other unpleasant sensations such as itching.
  • the formulations may release the largest dose of drug shortly after administration, for example, from 0 up to and including about 12 hours after administration, preferably from 0 to 8 hours. In another embodiment, the formulation releases the largest dose of drug from 0 to 6 hours. In a particular embodiment, the formulation provides an initial burst release within two hours. In another particular embodiment, the formulation provides an initial burst release within four hours. In still another particular embodiment, the formulation provides an initial burst release within six hours, and in still another particular embodiment, the formulation provides an initial burst release at about 8 hours. Earlier time period release may result in a more rapid onset of pain relief for the patient. A single dose irritation/pharmacokinetics study was conducted with
  • AUCo ⁇ t increased disproportionately in male and female rabbits when the dermal dose was increased from 30 to 300 mg/kg when lidocaine was delivered using either the ARC-31 or ARC-32 lidocaine gel, 40% formulation. It increased 1.7- to two-fold in male and female rabbits when the dose of the ARC-31 gel was increased to 1000 mg/kg. Cmax increased approximately 7- to 19-fold when the dose increased from 30 to 300 mg/kg using either gel. The median T max of lidocaine was 8 hours when the rabbits were dosed with the ARC-31 lidocaine gel; it decreased to 1 hour when the ARC-32 lldocaine gel was used.
  • the mean values of C max and AUCo- t of lidocaine between male and female animals were either comparable when the ARC- 31 gel was dosed or 42-50% higher in males when the ARC-32 gel was administered. Exposure to lidocaine, as measured using both Cmax and AUCO-t, was greater in rabbits dosed using the ARC-32 lidocaine gel compared to the ARC-31 lidocaine gel.
  • Intradermal Some of the formulation can be administered intradermally, using, for example, an insulin syringe. Care should be taken to administer the smallest dose possible, and in all cases, topical or intradermal, care should be taken to avoid systemic levels or local toxicity.
  • the preparation may be used for local topical delivery to any location where reduction of pain is required or desirable.
  • the formulations are used to treat pain, other than neuropathic pain. This would apply to pain cause by injuries, such as wounds and burns, and areas where medical procedure and cosmetic procedures are done. For example it would be desirable to use a rapidly acting anesthetic in a location where a patient has an abrasion, cut, puncture wound or other skin wound that causes pain. Burns cause pain and it would be desirable to reduce pain quickly through application of a rapidly acting local anesthetic.
  • Kits containing formulations from greater than about 20% to about 60% of the drug by weight of the formulation are described herein, ⁇ n one embodiment, the formulation contains about 40% by weight of lidocaine, in the form of the free base or a pharmaceutically acceptable salt.
  • the drug is in the form of the free base.
  • the kit may include a container containing the formulation, for example, in the form of a lotion, cream, ointment, gel, or foam.
  • the kit may further contain instructions for administering the formulation as well as medical devices or supplies for administering the formulation, such as gloves, applicators, such as a q-tip or swab, and combinations thereof.
  • Example 1 Determination of Solubility and Compatibility of Lidocaine and Lidocaine HCl in pharmaceutically acceptable topical carrier.
  • the primary goal was to develop a fast-acting topical product containing 40% Lidocaine as the Active Pharmaceutical Ingredient (API) with limited systemic exposure for the treatment of neuropathic pain.
  • API Active Pharmaceutical Ingredient
  • Materials and Methods The solubility and compatibility of lidocaine and lidocaine HCl in solvents typically used in topical pharmaceutical products was assessed in order to direct the formulation development efforts. The solvents were selected based on anticipated solubility parameters and solvent behavior, and their inclusion on the FDA approved Inactive Ingredient Guide (IIG). Additional attributes included the ability to accommodate a high level of drug while retaining adequate cosmetic properties, and the potential for a quick-drying product for application to the torso and face.
  • IIG Inactive Ingredient Guide
  • lidocaine and lidocaine hydrochloride were evaluated in single solvents with varying lipophil ⁇ c ⁇ ly. Given the high concentration of API, the solubilized drug samples were visually inspected following a week of storage to ensure no crystallization had occurred. Based on the single solvent data, a compatibility study was initiated to evaluate the chemical stability of the drug at a concentration of 40% w/w in a variety of solvent blends that would form the base of potential prototype gel or cream formulations. Both lidocaine and lidocaine hydrochloride retained their physical appearance and the absence of a drop in potency between the two week samples stored at accelerated conditions versus the initial samples supported the chemical compatibility of lidocaine in the solvent blends.
  • lidocaine or lidocaine hydrochloride was formulated at 40% w/w, shown in Tables 2 A and 2B.
  • four contained the lidocaine free base (both non-aqueous and aqueous gels), while the remaining seven formulations contained the HCl salt form of lidocaine (cream, gel, spray, and foam dosage forms).
  • the formulations were packaged in clear glass vials and stored at 5°C, 25°C, and 4O 0 C for a month. Separately, they were also subjected to three cycles each of freeze/thaw or hot/cold temperature cycling.
  • Example 2 /// Vitro Percutaneous Absorption of Lidocaine from Prototype Formulations Using Human Skin Materials and Methods Based on the results of Example 1 , eight prototype formulations were then selected and submitted for evaluation in an in vitro Skin Penetration Study. The purpose of this study was to characterize the in vitro percutaneous absorption of the actives (lidocaine free-base or lidocaine HCl) from prototype formulations, compared to two control formulations (a compounding pharmacy product and a marketed patch, LIDODERM®), following topical application to excised human skin from elective surgery.
  • actives lidocaine free-base or lidocaine HCl
  • LIDODERM® a compounding pharmacy product and a marketed patch
  • Percutaneous absorption was evaluated using this human abdominal tissue from a single donor, which was mounted in Bronaugh flow-through diffusion cells. The cells were maintained at a constant temperature of 32 0 C by use of recirculating water baths. These cells have a nominal diffusion area of 0.64 cm 2 .
  • Fresh receptor phase PBS with 0.1 % sodium azide and 4% Bovine Serum Albumin, was continuously pumped under the tissue at a flow rate of nominally 1.0 ml/hr and collected in 6-hour intervals. The receptor phase samples were collected in pre-weighed scintillation vials; the post weights were taken following the study duration. Following the 24-hour duration exposure, the formulation residing on the tissue surface was removed by tape-stripping with CuDerm D-Squame stripping discs.
  • Lidocaine residing in the epidermis, dermis, and receptor phase samples were properly labeled and were then sent to Pyxant Labs, Inc., an external contract bioanalytical laboratory, for subsequent analysis of Lidocaine content by LC/MS/MS and ultimate sample disposal.
  • Table 3 provides the composition of the formulations that were tested.
  • the mass of Lidocaine per square centimeter of dosed tissue was calculated using the mass of Lidocaine in each sample divided by the area of skin exposed to the formulation.
  • Tissue permeation results were statistically evaluated using unpaired student's t-tests (significant differences between formulations were defined by ap-value of ⁇ 0.05, at the 95% confidence interval).
  • Lidocaine delivery from all three gel (2749-30, 249-31 , and 2749-32) candidates was equivalent or better than the compounding pharmacy formulation, and lidocaine delivery from two of the gels (2749-32 and 2749-30) was comparable to the LIDODERM® patch over a 24 hour period.
  • the LIDODERM® patch demonstrated a more linear rate of drug permeation over the 24 hour period compared to the test formulations.
  • Formulations 2749-32 and 2749-30 delivered more lidocaine than all other formulations, including the LIDODERM® patch, from time of application to 6 hours. This indicates that these two formulations may have a faster onset of action and thus should provide more rapid pain relief.
  • Formulation 31 had comparable delivery profile to the compounding pharmacy cream. Prototype candidates containing Lidocaine HCl did not deliver as well as the formulations containing the free base.
  • Skin permeation (receptor phase levels) of Lidocaine ranged from 2.8 to 35 ⁇ g/cm 2 from Formulations 2749-72 and 2749-30, respectively.
  • Formulations 2749-32 and 2749-30 had the highest permeation amount of Lidocaine with 34 and 35 ⁇ g/cm 2 , respectively.
  • Lidocaine delivery from Formulations 2749-32 and 2749-30 were comparable to the LIDODERM® patch, 34 ⁇ g/cm 2 .
  • Tissue permeation of Lidocaine from the control formulations (Compounding Pharmacy Product and Lidocaine Patch) was 24 and 34 ⁇ g/cm 2 (equivalent to 1.4 and 0.68 percent of the applied dose of Lidocaine), respectively.
  • Cutaneous delivery of Lidocaine following 24 hours exposure from Formulations 2749-32 and 2749-30 was comparable to the Lidocaine Patch.
  • Skin permeation of Lidocaine from Formulations 2749- 32 and 2749-30 as well as the LIDODERM® patch was significantly higher (p ⁇ 0.05, unpaired student's t-test) than the Compounding Pharmacy Product, 24 ⁇ g/cm 2 .
  • Skin permeation from Formulation 2749-31 (21 ⁇ g/cm 2 ) was comparable to that of the Compounding Pharmacy Product.
  • Figure 1 is a graph of the cumulative penetration of lidocaine through human skin, measured as micrograms lidocaine/cm 2 , over time in hours.
  • Table 4 shows the cumulative receptor phase levels of lidocaine in percent of applied dose.
  • Lidocaine-contammg gels exhibited greater cumulative penetration of lidocaine than lidocaine HCl-contain ⁇ ng creams and sprays.
  • LIDODERM® a commercially available patch comprised of an adhesive material containing 5% lidocaine, which is applied to a non-woven polyester felt backing and covered with a polyethylene terephthalate (PET) film release liner, is applied only once for up to 12 hours in a given 24 hour period.
  • PET polyethylene terephthalate
  • the Lidocaine GeI formulations 2749-32 and 2749-30 gave the highest levels of Lidocaine delivery of all semisolid dosage forms tested and the total amount of Lidocaine delivered over 24 hours from these two gel formulations was comparable to that achieved with the marketed LIDODERM® patch.
  • Formulations 2749-32 and 2749-30 delivered more lidocaine than all other formulations, including the LIDODERM® patch, from time of application to 6 hours. This indicates that these two formulations may have a faster onset of action and thus should provide more rapid pain relief.
  • the objective of this study was to determine the potential toxicity and partial pharmacokinetic profile of two formulations of Lidocaine Gel, 40% following a single dermal application followed by a 14-day observation period.
  • ARC-31 and ARC-32 correspond to formulations 2749-31 and 2749- 31 described above.
  • New Zealand white rabbits (24 male and 24 female, plus 4/sex alternates) were supplied by Charles River Laboratories and were 3-4 months of age on Study Day 1 (day of dosing). Males weighed between 2.7 and 3.3 kg and females weighed between 2.7 and 3.2 kg. Identification was by ear tag and color-coded cage card. The animals were acclimated for a minimum of 5 days prior to Study Day 1 and were acclimated to the Elizabethan collars at least once for at least 3 hours prior to Study Day 1. The animals were housed individually in stainless steel cages that conformed to standards set forth in the Animal Welfare Act (with all amendments) and the Guide for the Care and Use of Laboratory Animals (National Academy Press, Washington, D.C., 1996).
  • Purina Certified Rabbit Diet # PMI 5325 was provided ad libitum 17O g per day after acclimation. Filtered tap water was provided ad libitum.
  • Environmental controls were set to maintain temperatures of 16°C to 22°C with a relative humidity of 30% to 70%. A 12-hour light/12-hour dark cycle was maintained, except when interrupted to accommodate other study procedures. Ten or greater air changes per hour with 100% fresh air was maintained in the animal room.
  • Animals were randomly assigned to groups by a computerized weight-ordered distribution such that the group-mean body weights did not exceed ⁇ 10% of the overall mean weight for each sex at the time of randomization.
  • Plasma concentrations of lidocaine were determined using a validated LC-MS/MS method.
  • the lower limit of quantitation (LLOQ) and upper limit of quantitation (ULOQ) were 10 and 5000 ng/mL, respectively.
  • Bioanalysis was conducted at Frontage Laboratories, Inc. (Malvern, PA). Bioanalytical data were captured using Analyst (version 1.4., Applied Biosystems) and Watson LIMS (version 7.3). Raw data are stored at the Central File of Frontage Laboratories, Inc. (Malvern, PA). Toxicokinetic Calculations
  • the mean plasma concentrations of lidocaine are presented in Table 6 are displayed in Figures 2 (ARC-31) and 3 (ARC-32).
  • the mean pharmacokinetic parameters are in Table 8.
  • AUCo-t and C max versus dose are displayed in Figures 4 and 5.
  • Measurable concentrations of lidocaine above the LLOQ (10 ng/niL) were detected in 16 of 60 plasma samples collected from animals that received only the vehicle. Six of these animals were administered the ARC- 31 vehicle and ten received the ARC-32 vehicle. Values ranged from two to 23 times the LLOQ. When the control samples with measurable concentrations were reassayed, the concentrations were not different from the initial results, based on the SOP for the reanalysis of samples. None of the samples collected pre-dose contained measurable concentrations of Hdocaine.
  • the mean C max of lidocaine in male rabbits administered the compound dermally in the ARC-31 gel increased from 83.546 to 1626.184 ng/mL when the dose increased from 30 (Group 2) to 300 mg/kg (Group 3), a 19-fold increase (Table 6, Figure 2A).
  • Increasing the dose further to 1000 mg/kg (Group 4) increased C max only 1.4-fold to 2253.274 ng/mL.
  • AUCo- t was also disproportionately greater (63 -fold) when the dose increased from
  • AUCo- t increased only 1.7-fold (31382.922 ng-hr/mL) when the dose increased from 300 to 1000 mg/kg.
  • the median T max occurred at 8 hours post-dose at all three dose levels.
  • the mean C max of lidocaine increased ten-fold from 166.753 to 1726.581 ng/mL when the dermal dose increased from 30 to 300 mg/kg (Table 6, Figure 2B). It increased approximately two-fold to 3336.581 ng/mL when the dose increased to 1000 mg/kg (Table 6).
  • T max was 8 hours post-dose at all three dose levels.
  • the elimination half-life was measurable in only one animal at the
  • ARC-32 Lidocaine Gel The mean C max value of lidocaine in male rabbits increased 7.6-fold when the dose in the ARC-32 lidocaine gel increased from 30 to 300 mg/kg
  • AUC0-t increased disproportionately from 3270.930 to 53694.539 ng-hr/mL, a 16-fold increase (Table 7).
  • the median T max occurred at 1 hour post-dose, the first sample time-point, for all 3 doses.
  • the mean VA value at the 30 mg/kg dose was 6.6 hours and 2.5 hours at the 300 mg/kg dose (Table 7).
  • the mean concentration in male rabbits was 13201.466 ng/niL and 15709.008 ng/mL in females. These values are approximately 3- to 4-fold higher than in rabbits dosed at 300 mg/kg.
  • Plasma samples were collected from one female and two male rabbits that were moribund; lidocaine concentrations ranged from approximately 12,000 to 25,600 ng/mL.
  • the C max of lidocaine was seven-fold higher for the ARC-32 gel compared to the ARC-31 gel at the 30 mg/kg dose (617.700 and 83.546 ng/mL, respectively) and approximately three-fold at the 300 mg/kg dose level (4719.600 and 1626.184 ng/mL) (Figure 4).
  • AUC 0 ⁇ t was elevenfold higher at the 30 mg/kg dose (3270.930 and 290.137 ng-hr/mL) and three-fold higher at the 300 mg/kg dose level (53694.539 and 18224.512 ng-hr/mL) when lidocaine was delivered using the ARC-32 gel compared to the ARC-31 gel ( Figure 5).
  • the C max of lidocaine was 2.5-fold higher when the
  • ARC-32 gel was used compared to the ARC-31 gel at the 30 mg/kg dose (412.280 and 166.753 ng/mL, respectively) and almost two-fold at the 300 mg/kg dose (3178.373 and 1726.581 ng/mL) (Figure 4).
  • AUC 04 was approximately five-fold higher at the 30 mg/kg dose (2180.202 and 453.608 ng-hr/mL) and two-fold higher at the 300 mg/kg dose (37829.709 and
  • AUCo- t increased disproportionately in male and female rabbits when the dermal dose was increased from 30 to 300 mg/kg when lidocaine was delivered using either the ARC-31 or ARC-32 lidocaine gel, 40% formulation. It increased 1.7- to two-fold in male and female rabbits when the dose of the ARC-31 gel was increased to 1000 mg/kg.
  • C max increased approximately 7- to 19-fold when the dose increased from 30 to 300 mg/kg using either gel.
  • the median T max of lidocaine was 8 hours when the rabbits were dosed with the ARC-31 lidocaine gel; it decreased to 1 hour when the ARC- 32 lidocaine gel was used.
  • the mean values of C max and AUCo-t of lidocaine between male and female animals were either comparable when the ARC-31 gel was dosed or 42-50% higher in males when the ARC-32 gel was administered. Exposure to lidocaine, as measured using both C max and AUCo-t, was greater in rabbits dosed using the ARC-32 lidocaine gel compared to the ARC-31 lidocaine gel.
  • Example 4 Biocompatibility Study in New Zealand White Rabbits with Two Formulations of Lidocaine Gel, 40% A biocompatibility study of two lidocaine gel formulations containing 40% lidocaine was conducted. The study was conducted as described in Example 3.
  • Lidocaine Gel 40% showed any test article-related findings through the termination of the study on Study Day 4.
  • ARC-32 Lidocaine Gel 40% all six animals receiving 1000 mg/kg died early or were euthanized as moribund on Study Day 1.
  • animals at 300 mg/kg and 1000 mg/kg were observed with neurological- related signs of abnormal gait, decreased activity, convulsions, loss of righting reflex, labored breathing, gasping, rales, and/or increased salivation and the exposure period for these animals was terminated.
  • animals at 1000 mg/kg did not appear to be recovering and were euthanized or died; animals at 300 mg/kg did show signs of recovery and remained on study.
  • redness of the back/application site was noted in five of six animals receiving the ARC-32 vehicle control and five of six animals at 300 mg/kg ARC-32. This redness was typically seen on Study Days 2, 3, and 4 and was correlated by dermal scores of very slight to severe erythema. Because the redness was seen in the vehicle control group, it is likely that the vehicle control or the amount of vehicle control applied was partially responsible for the redness noted at 300 mg/kg; only two of six animals at 30 mg/kg ARC-32 had redness. Swelling of the back was also noted in animals at 300 mg/kg ARC- 32 and correlated to very slight edema noted on Study Days 2, 3, and 4. All animals at 1000 mg/kg ARC-32 and one male at 300 mg/kg
  • ARC-32 had red discoloration of the treated skin that was collected from the application site at necropsy. Organ weights were not affected by administration of either of the test articles.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Emergency Medicine (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Anesthesiology (AREA)
  • Inorganic Chemistry (AREA)
  • Rheumatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une préparation anesthésique topique transdermique, qui peut être utilisée pour atténuer ou inhiber la douleur. Dans le mode préféré de réalisation, l'anesthésique topique est un anesthésique local comme de la lidocaïne, de la manière la plus préférée une base libre de lidocaïne dans un gel, et le dosage de l'anesthésique local est efficace dans la zone douloureuse ou des zones immédiatement adjacentes, pour atténuer ou éliminer la douleur. Une concentration élevée d'anesthésique local en solution dans le support est utilisée pour provoquer une libération et une prise rapide du médicament. Une libération est typiquement obtenue pendant une période de plusieurs heures.
PCT/US2009/054054 2008-08-15 2009-08-17 Préparations anesthésiques locales à concentration élevée WO2010019953A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US8934808P 2008-08-15 2008-08-15
US61/089,348 2008-08-15

Publications (1)

Publication Number Publication Date
WO2010019953A1 true WO2010019953A1 (fr) 2010-02-18

Family

ID=41268476

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2009/054054 WO2010019953A1 (fr) 2008-08-15 2009-08-17 Préparations anesthésiques locales à concentration élevée

Country Status (2)

Country Link
US (5) US8119694B2 (fr)
WO (1) WO2010019953A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013138509A1 (fr) 2012-03-13 2013-09-19 The Johns Hopkins University Protéines cérébrales et neurologiques citrullinées en tant que biomarqueurs de lésions cérébrales ou de neurodégénérescence
US10758502B2 (en) 2008-08-15 2020-09-01 Centrexion Therapeutics Corporation High concentration local anesthetic formulations

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2008289109B2 (en) * 2007-08-17 2012-02-02 Centrexion Therapeutics Corporation High concentration local anesthetic formulations
CN106109444B (zh) * 2010-11-09 2019-12-13 张洁 薄层和液体结合的透皮给药系统
US9226954B2 (en) 2011-07-20 2016-01-05 Joseph C. McGinley Method for treating and confirming diagnosis of exertional compartment syndrome
US9138188B2 (en) * 2011-07-20 2015-09-22 Joseph C. McGinley Method for treating and confirming diagnosis of exertional compartment syndrome
US9138194B1 (en) 2012-06-27 2015-09-22 Joseph McGinley Apparatus for use to replicate symptoms associated with vascular obstruction secondary to vascular compression
US9801945B2 (en) 2014-04-21 2017-10-31 Heron Therapeutics, Inc. Long-acting polymeric delivery systems
SI3134070T1 (sl) 2014-04-21 2021-03-31 Heron Therapeutics, Inc. Sestave poliortoestra in pomožne snovi iz organske kisline
WO2018048460A1 (fr) 2014-04-21 2018-03-15 Heron Therapeutics, Inc. Composition pharmaceutique comprenant un système d'administration, un anesthésique local de type amide et un méloxicam
KR20220138419A (ko) 2014-04-21 2022-10-12 헤론 테라퓨틱스 인코포레이티드 장기간 작용하는 중합체 전달 시스템
US11446236B2 (en) 2015-08-05 2022-09-20 Cmpd Licensing, Llc Topical antimicrobial compositions and methods of formulating the same
US11793783B2 (en) 2015-08-05 2023-10-24 Cmpd Licensing, Llc Compositions and methods for treating an infection
US11684567B2 (en) 2015-08-05 2023-06-27 Cmpd Licensing, Llc Compositions and methods for treating an infection
US10039830B2 (en) 2016-03-04 2018-08-07 Cetylite Industries, Inc. Topical anesthetic composition
US10966946B2 (en) 2016-11-17 2021-04-06 Cmpd Licensing, Llc Compounded compositions and methods for treating pain
US11737975B2 (en) * 2016-11-17 2023-08-29 Cmpd Licensing, Llc Compounded compositions and methods for treating pain
US11986448B2 (en) 2016-11-17 2024-05-21 Cmpd Licensing, Llc Compounded compositions and methods for treating pain
WO2022107084A1 (fr) * 2020-11-21 2022-05-27 Cellix Bio Private Limited Compositions pharmaceutiques destinées à être utilisées dans la gestion et le traitement de la douleur
US11992483B2 (en) * 2021-03-31 2024-05-28 Cali Biosciences Us, Llc Emulsions for local anesthetics

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0388306A2 (fr) * 1989-03-17 1990-09-19 Hind Health Care, Inc. Méthode de traitement de la douleur associée à l'herpès-zoster et de la neuralgie postherpétique par l'application topique d'anesthésiques locaux
US5411738A (en) * 1989-03-17 1995-05-02 Hind Health Care, Inc. Method for treating nerve injury pain associated with shingles (herpes-zoster and post-herpetic neuralgia) by topical application of lidocaine
WO2000069471A1 (fr) * 1999-05-19 2000-11-23 The University Of Georgia Research Foundation, Inc. Anesthesie transcutanee amelioree au moyen d'agents anesthesiques locaux
US6461644B1 (en) * 1996-03-25 2002-10-08 Richard R. Jackson Anesthetizing plastics, drug delivery plastics, and related medical products, systems and methods
US7018647B1 (en) * 1999-12-27 2006-03-28 Teikoku Seiyaku Co., Ltd Patches for external use
WO2009026178A2 (fr) * 2007-08-17 2009-02-26 Arcion Therapeutics, Inc. Formulations anesthésiques locales à concentration élevée

Family Cites Families (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1165240A (fr) 1980-07-09 1984-04-10 The Procter & Gamble Company Composes pharmaceutiques a usage topique
JPS6185315A (ja) 1984-10-04 1986-04-30 Teikoku Seiyaku Kk シ−ト状製剤
US4863721A (en) 1987-05-22 1989-09-05 The Procter & Gamble Company Reduced stinging antiperspirant compositions
US4752466A (en) 1987-08-31 1988-06-21 Johnson & Johnson Products, Inc. Thrombin aerosol
US5380754A (en) 1988-02-29 1995-01-10 Virotex Corporation Topical composition enhancing healing of viral lesions
US4814168A (en) 1988-03-04 1989-03-21 Noven Pharmaceuticals, Inc. Transdermal multipolymer drug delivery system
US5656286A (en) 1988-03-04 1997-08-12 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
US5719197A (en) 1988-03-04 1998-02-17 Noven Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
US5474783A (en) 1988-03-04 1995-12-12 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
US4994267A (en) 1988-03-04 1991-02-19 Noven Pharmaceuticals, Inc. Transdermal acrylic multipolymer drug delivery system
US5300291A (en) 1988-03-04 1994-04-05 Noven Pharmaceuticals, Inc. Method and device for the release of drugs to the skin
US5234957A (en) 1991-02-27 1993-08-10 Noven Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
JP3115625B2 (ja) 1991-03-30 2000-12-11 帝國製薬株式会社 リドカイン含有外用貼付剤
SE9200762D0 (sv) 1992-03-12 1992-03-12 Astra Ab New topical use
DK82892D0 (da) 1992-06-24 1992-06-24 Michael Hansen Anvendelse af braadgifte fra bier og hvepse til fremstilling af laegemidler til behandling af infektioner
US5922340A (en) * 1992-09-10 1999-07-13 Children's Medical Center Corporation High load formulations and methods for providing prolonged local anesthesia
US5415866A (en) 1993-07-12 1995-05-16 Zook; Gerald P. Topical drug delivery system
US5807568A (en) 1994-12-27 1998-09-15 Mcneil-Ppc, Inc. Enhanced delivery of topical compositions containing flurbiprofen
DE19526864A1 (de) 1995-07-22 1997-01-23 Labtec Gmbh Hormonpflaster
US5667799A (en) 1995-10-30 1997-09-16 Caldwell; Larry J. Method for treating headache pain with topical local anesthetic compositions
JPH09268123A (ja) 1996-03-30 1997-10-14 Nichiban Co Ltd 局所麻酔用貼付剤
US5814659A (en) 1996-04-23 1998-09-29 Dtr Dermal Therapy (Barbados) Inc. Topical analgesic composition
FR2748207B1 (fr) 1996-05-06 1998-06-12 Cird Galderma Composition a base d'un compose modulant la reactivite des fibres nerveuses
US5955097A (en) 1996-10-18 1999-09-21 Virotex Corporation Pharmaceutical preparation applicable to mucosal surfaces and body tissues
US5948433A (en) 1997-08-21 1999-09-07 Bertek, Inc. Transdermal patch
US6103266A (en) 1998-04-22 2000-08-15 Tapolsky; Gilles H. Pharmaceutical gel preparation applicable to mucosal surfaces and body tissues
CA2318047A1 (fr) 1998-10-05 2000-04-13 Yutoku Pharmaceutical Ind. Co., Ltd. Bande pour absorption percutanee
US6962691B1 (en) 1999-05-20 2005-11-08 U & I Pharmaceuticals Ltd. Topical spray compositions
US20040131665A1 (en) * 1999-10-22 2004-07-08 Wepfer Scott T. Topical anesthetic formulation
US6383511B1 (en) * 1999-10-25 2002-05-07 Epicept Corporation Local prevention or amelioration of pain from surgically closed wounds
US6432415B1 (en) 1999-12-17 2002-08-13 Axrix Laboratories, Inc. Pharmaceutical gel and aerosol formulations and methods to administer the same to skin and mucosal surfaces
WO2001054679A2 (fr) 2000-01-27 2001-08-02 Children's Hospital Research Foundation Composition d'anesthesique et de vasodilatateur transdermique et procedes pour son administration topique
JP2004521111A (ja) * 2001-01-25 2004-07-15 ユーロ−セルティーク，エス．エイ． 局所麻酔薬および使用法
CA2446060A1 (fr) * 2001-05-07 2002-11-14 Corium International Compositions et systemes d'administration d'un anesthesique local
US20030138490A1 (en) * 2001-09-08 2003-07-24 Zhibing Hu Synthesis and uses of polymer gel nanoparticle networks
US6894078B2 (en) 2001-09-17 2005-05-17 James G. Castillo Alcohol based topical anesthetic formulation and method
US6676961B1 (en) 2002-03-06 2004-01-13 Automated Carrier Technologies, Inc. Transdermal patch assembly
AU2003225745A1 (en) * 2002-03-12 2003-09-29 Neurogesx, Inc. Free-base formulations of local anesthetics
EP1592420B1 (fr) * 2003-01-24 2014-01-01 Stiefel Research Australia Pty Ltd Mousse de phosphate de clindamycine
US20040214215A1 (en) 2003-03-07 2004-10-28 Yu Ruey J. Bioavailability and improved delivery of alkaline pharmaceutical drugs
DE602004012718T2 (de) 2003-03-20 2009-05-07 Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield Formulierung für einen dosierinhalator unter verwendung von hydro-fluoro-alkanen als treibstoffe
ES2535045T3 (es) 2003-04-10 2015-05-04 Vanderbilt Royalty Sub L.P. Usos y composiciones para administración de capsaicina
US20050014823A1 (en) 2003-07-17 2005-01-20 Soderlund Patrick L. Topical anesthetic composition and method of administration
US20050175709A1 (en) * 2003-12-11 2005-08-11 Baty Ace M.Iii Therapeutic microparticles
CN102091079B (zh) * 2005-06-03 2014-03-12 艾克若克斯Dds有限公司 用于透皮给药的方法和组合物
WO2007025142A2 (fr) 2005-08-26 2007-03-01 Ladd Byron S Compositions et procedes pour le traitement de surface dans des procedures medicales et chirurgicales
GT200600396A (es) * 2005-09-07 2007-04-23 Dispositivos para la aplicacion de medicamentos transdermicos conteniendo o-desmetil venlafaxina (odv) o sus sales
GB0518769D0 (en) 2005-09-14 2005-10-19 Medpharm Ltd Topical formulations
JP2006298934A (ja) 2006-06-26 2006-11-02 Larry J Caldwell 局所的局所麻酔薬組成物を用いる頭痛の痛みを処置するための方法
US8119694B2 (en) 2008-08-15 2012-02-21 Arcion Therapeutics, Inc. High concentration local anesthetic formulations
JP5453064B2 (ja) 2009-11-25 2014-03-26 株式会社北里バイオファルマ 動物細胞のガラス化凍結保存液

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0388306A2 (fr) * 1989-03-17 1990-09-19 Hind Health Care, Inc. Méthode de traitement de la douleur associée à l'herpès-zoster et de la neuralgie postherpétique par l'application topique d'anesthésiques locaux
US5411738A (en) * 1989-03-17 1995-05-02 Hind Health Care, Inc. Method for treating nerve injury pain associated with shingles (herpes-zoster and post-herpetic neuralgia) by topical application of lidocaine
US6461644B1 (en) * 1996-03-25 2002-10-08 Richard R. Jackson Anesthetizing plastics, drug delivery plastics, and related medical products, systems and methods
WO2000069471A1 (fr) * 1999-05-19 2000-11-23 The University Of Georgia Research Foundation, Inc. Anesthesie transcutanee amelioree au moyen d'agents anesthesiques locaux
US7018647B1 (en) * 1999-12-27 2006-03-28 Teikoku Seiyaku Co., Ltd Patches for external use
WO2009026178A2 (fr) * 2007-08-17 2009-02-26 Arcion Therapeutics, Inc. Formulations anesthésiques locales à concentration élevée

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
ARPEY C J ET AL: "Advances in local anesthesia", CLINICS IN DERMATOLOGY, J.B. LIPPINCOTT, PHILADELPHIA, PA, US, vol. 10, no. 3, 1 July 1992 (1992-07-01), pages 275 - 283, XP026431387, ISSN: 0738-081X, [retrieved on 19920701] *
BAGESUND M, TABRIZI P.: "Lidocaine 20% patch vs lidocaine 5% gel for topical anaesthesia of oral mucosa (Abstract)", 12 March 2008 (2008-03-12), XP002556939, Retrieved from the Internet <URL:http://www.ncbi.nlm.nih.gov/pubmed/18341564?dopt=AbstractPlus> [retrieved on 20091123] *
BÅGESUND MATS ET AL: "Lidocaine 20% patch vs lidocaine 5% gel for topical anaesthesia of oral mucosa.", INTERNATIONAL JOURNAL OF PAEDIATRIC DENTISTRY / THE BRITISH PAEDODONTIC SOCIETY [AND] THE INTERNATIONAL ASSOCIATION OF DENTISTRY FOR CHILDREN NOV 2008, vol. 18, no. 6, November 2008 (2008-11-01), pages 452 - 460, XP007910616, ISSN: 1365-263X *
CHEMISCHE FABRIK KREUSSLER AND CO GMBH: "Dynexan Mundgel", May 2005 (2005-05-01), XP002556688, Retrieved from the Internet <URL:www.cmsite.de/de/dynexan_mundgel.html> [retrieved on 20091120] *
EIDELMAN A ET AL: "Topical anesthetics for dermal instrumentation: A systematic review of randomized, controlled trials", ANNALS OF EMERGENCY MEDICINE 200510 US, vol. 46, no. 4, October 2005 (2005-10-01), pages 343 - 351, XP005087422, ISSN: 0196-0644 *
GALER B ET AL: "A randomized, open-label study comparing the efficacy and safety of lidocaine patch 5% with celecoxib 200 mg in patients with pain from osteoarthritis of the knee", JOURNAL OF PAIN, SAUNDERS, PHILADELPHIA, PA, US, vol. 6, no. 3, 1 March 2005 (2005-03-01), pages S51, XP004796313, ISSN: 1526-5900 *
GALER B ET AL: "Lidocaine patch 5% improves outcomes for low-back pain and osteoarthritis patients receiving COX-2-selective or traditional NSAID therapy for pain relief", JOURNAL OF PAIN, SAUNDERS, PHILADELPHIA, PA, US, vol. 6, no. 3, 1 March 2005 (2005-03-01), pages S50, XP004796310, ISSN: 1526-5900 *
KASAJ A ET AL: "Effectiveness of a topical salve (Dynexan) on pain sensitivity and early wound healing following nonsurgical periodontal therapy.", EUROPEAN JOURNAL OF MEDICAL RESEARCH 29 MAY 2007, vol. 12, no. 5, 29 May 2007 (2007-05-29), pages 196 - 199, XP009126170, ISSN: 0949-2321 *
MARRA D E ET AL: "Systemic toxicity from topically applied Lidocaine in conjunction with fractional photothermolysis", ARCHIVES OF DERMATOLOGY, AMERICAN MEDICAL ASSOCIATION, US, vol. 142, 1 January 2006 (2006-01-01), pages 1024 - 1026, XP002509848, ISSN: 0003-987X *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10758502B2 (en) 2008-08-15 2020-09-01 Centrexion Therapeutics Corporation High concentration local anesthetic formulations
US11517546B2 (en) 2008-08-15 2022-12-06 Centrexion Therapeutics Corporation High concentration local anesthetic formulations
WO2013138509A1 (fr) 2012-03-13 2013-09-19 The Johns Hopkins University Protéines cérébrales et neurologiques citrullinées en tant que biomarqueurs de lésions cérébrales ou de neurodégénérescence

Also Published As

Publication number Publication date
US10758502B2 (en) 2020-09-01
US20210177782A1 (en) 2021-06-17
US20170014359A1 (en) 2017-01-19
US9370500B2 (en) 2016-06-21
US20180296506A1 (en) 2018-10-18
US20100041765A1 (en) 2010-02-18
US20120149779A1 (en) 2012-06-14
US11517546B2 (en) 2022-12-06
US8119694B2 (en) 2012-02-21

Similar Documents

Publication Publication Date Title
US11517546B2 (en) High concentration local anesthetic formulations
US20200338064A1 (en) High concentration local anesthetic formulations
US7425340B2 (en) Permeation enhancing compositions for anticholinergic agents
EP3746086A1 (fr) Formulations topiques comprenant du tofacitinib
US20210137830A1 (en) Topical detomidine formulations
WO2010010168A1 (fr) Compositions pharmaceutiques transdermiques renfermant du danazol
TW202002977A (zh) 治療搔癢症的組合物與方法
US8563616B2 (en) Desensitizing drug product
US20050158371A1 (en) Novel external agent
US20240100045A1 (en) Emulsion composition and uses thereof in the prevention and/or treatment of skin damage caused by radiation
TW202202129A (zh) 含麻醉藥物活性成分的透皮製劑及其製備方法
KR20230026449A (ko) (1s)-1-페닐-2-피리딘-2-일레탄아민의 국소 제형
US20220409634A1 (en) Topical pharmaceutical formulation
AU2012202327A1 (en) High concentration local anesthetic formulations
KR20220124175A (ko) 건선 및 기타 질병 치료를 위한 국소 시클로스포린
CN117618406A (zh) 一种局部麻醉制剂组合物及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09791585

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09791585

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载